Insomnia Disorder
Conditions
Brief summary
The main purpose of this study is to assess efficacy and safety of ACT-541468 (daridorexant) in adult and elderly subjects with insomnia disorder. Efficacy will be evaluated on objective and subjective sleep parameters.
Interventions
Daridorexant will be administered as tablets, orally, once daily in the evening.
Daridorexant will be administered as tablets, orally, once daily in the evening.
OTHERPlacebo
Matching placebo will be administered as tablets, orally, once daily in the evening.
Sponsors
Idorsia Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent prior to any study-mandated procedure; * Male or female aged ≥ 18 years; * Insomnia disorder according to DSM-5 criteria; * Insomnia Severity Index score ≥ 15; * Insufficient sleep quantity as collected subjectively in the sleep diary; * Women of childbearing potential must have a negative and urine pregnancy test and use the contraception scheme up to at least 30 days after last study treatment intake.
Exclusion criteria
* Body mass index below 18.5 or above 40.0 kg/m2; * Any lifetime history of of related breathing disorder, periodic limb movement disorder, restless legs syndrome, circadian rhythm disorder, rapid eye movement (REM) behavior disorder, narcolepsy, or apnea/ hypopnea; * Cognitive behavioral therapy (CBT) only allowed if, the treatment started at least 1 month prior to Visit 3 and the subject agrees to continue this CBT throughout the study; * Self-reported usual daytime napping ≥ 1 hour per day and ≥ 3 days per week; * Acute or unstable psychiatric conditions diagnosed by the Mini International Neuropsychiatric Interview; * Mini Mental State Examination (MMSE) score \< 25 in subjects ≥ 50 years; * For female subjects: pregnant, lactating or planning to become pregnant during projected duration of the study; * History or clinical evidence of any disease or medical condition or treatment, which may put the subject at risk of participation in the study or may interfere with the study assessments. * Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 3 in Latency to Persistent Sleep (LPS) | From baseline to Month 3 (i.e. for up to 3 months) | Latency to Persistent Sleep is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography. |
| Change From Baseline to Month 1 in Wake After Sleep Onset (WASO) (Sleep Maintenance) | From baseline to Month 1 (i.e. for up to 1 month) | Wake After Sleep Onset is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography. |
| Change From Baseline to Month 3 in Wake After Sleep Onset (WASO) | From baseline to Month 3 (i.e. for up to 3 months) | Wake After Sleep Onset is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography. |
| Change From Baseline to Month 1 in Latency to Persistent Sleep (LPS) (Sleep Onset) | From baseline to Month 1 (i.e. for up to 1 month) | Latency to Persistent Sleep is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 1 in the Subjective Total Sleep Time (sTST) | From baseline to Month 1 (i.e. for up to 1 month) | Subjective Total Sleep Time is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time. |
| Change From Baseline to Month 3 in the Subjective Total Sleep Time (sTST) | From baseline to Month 3 (i.e. for up to 3 months) | Subjective Total Sleep Time is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time. |
| Change From Baseline to Month 1 in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score | From baseline to Month 1 (i.e. for up to 1 month) | The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening. |
| Change From Baseline to Month 3 in IDSIQ Sleepiness Domain Score | From baseline to Month 3 (i.e. for up to 3 months) | The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening. |
Countries
Australia, Canada, Denmark, Germany, Italy, Poland, Serbia, Spain, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daridorexant 25 mg Daridorexant was administered as tablets, orally, once daily in the evening. | 310 |
| Daridorexant 50 mg Daridorexant was administered as tablets, orally, once daily in the evening. | 310 |
| Placebo Matching placebo was administered as tablets, orally, once daily in the evening. | 310 |
| Total | 930 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 7 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 | 3 |
| Overall Study | Other reasons | 3 | 11 | 8 |
| Overall Study | Withdrawal by Subject | 13 | 10 | 12 |
Baseline characteristics
| Characteristic | Total | Daridorexant 25 mg | Placebo | Daridorexant 50 mg |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 364 Participants | 121 Participants | 122 Participants | 121 Participants |
| Age, Categorical Between 18 and 65 years | 566 Participants | 189 Participants | 188 Participants | 189 Participants |
| Age, Continuous | 55.4 years STANDARD_DEVIATION 15.3 | 55.8 years STANDARD_DEVIATION 15.3 | 55.1 years STANDARD_DEVIATION 15.4 | 55.5 years STANDARD_DEVIATION 15.3 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 3 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 77 Participants | 19 Participants | 28 Participants | 30 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 146 Participants | 51 Participants | 51 Participants | 44 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 783 Participants | 259 Participants | 259 Participants | 265 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 839 Participants | 287 Participants | 278 Participants | 274 Participants |
| Sex: Female, Male Female | 624 Participants | 215 Participants | 210 Participants | 199 Participants |
| Sex: Female, Male Male | 306 Participants | 95 Participants | 100 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 310 | 0 / 308 | 0 / 309 |
| other Total, other adverse events | 44 / 310 | 41 / 308 | 35 / 309 |
| serious Total, serious adverse events | 2 / 310 | 3 / 308 | 7 / 309 |
Outcome results
Primary
Change From Baseline to Month 1 in Latency to Persistent Sleep (LPS) (Sleep Onset)
Latency to Persistent Sleep is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography.
Time frame: From baseline to Month 1 (i.e. for up to 1 month)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 1 in Latency to Persistent Sleep (LPS) (Sleep Onset) | -28.17 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 1 in Latency to Persistent Sleep (LPS) (Sleep Onset) | -31.20 minutes |
| Placebo | Change From Baseline to Month 1 in Latency to Persistent Sleep (LPS) (Sleep Onset) | -19.85 minutes |
Comparison: Between-treatment analysis for change from baseline in LPS (min) to Month 1 (Daridorexant 25 mg vs placebo).p-value: 0.000595% CI: [-13.014, -3.629]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in LPS (min) to Month 1 (Daridorexant 50 mg vs placebo).p-value: <0.000195% CI: [-16.022, -6.687]Mixed Models Analysis
Primary
Change From Baseline to Month 1 in Wake After Sleep Onset (WASO) (Sleep Maintenance)
Wake After Sleep Onset is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography.
Time frame: From baseline to Month 1 (i.e. for up to 1 month)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 1 in Wake After Sleep Onset (WASO) (Sleep Maintenance) | -18.40 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 1 in Wake After Sleep Onset (WASO) (Sleep Maintenance) | -28.98 minutes |
| Placebo | Change From Baseline to Month 1 in Wake After Sleep Onset (WASO) (Sleep Maintenance) | -6.20 minutes |
Comparison: Between-treatment analysis for change from baseline in WASO (min) to Month 1 (Daridorexant 25 mg vs placebo).p-value: <0.000195% CI: [-17.435, -6.961]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in WASO (min) to Month 1 (Daridorexant 50 mg vs placebo).p-value: <0.000195% CI: [-27.996, -17.567]Mixed Models Analysis
Primary
Change From Baseline to Month 3 in Latency to Persistent Sleep (LPS)
Latency to Persistent Sleep is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography.
Time frame: From baseline to Month 3 (i.e. for up to 3 months)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 3 in Latency to Persistent Sleep (LPS) | -30.73 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 3 in Latency to Persistent Sleep (LPS) | -34.80 minutes |
| Placebo | Change From Baseline to Month 3 in Latency to Persistent Sleep (LPS) | -23.13 minutes |
Comparison: Between-treatment analysis for change from baseline in LPS (min) to Month 3 (Daridorexant 25 mg vs placebo).p-value: 0.001595% CI: [-12.265, -2.923]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in LPS (min) to Month 3 (Daridorexant 50 mg vs placebo).p-value: <0.000195% CI: [-16.348, -6.994]Mixed Models Analysis
Primary
Change From Baseline to Month 3 in Wake After Sleep Onset (WASO)
Wake After Sleep Onset is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography.
Time frame: From baseline to Month 3 (i.e. for up to 3 months)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 3 in Wake After Sleep Onset (WASO) | -22.97 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 3 in Wake After Sleep Onset (WASO) | -29.41 minutes |
| Placebo | Change From Baseline to Month 3 in Wake After Sleep Onset (WASO) | -11.11 minutes |
Comparison: Between-treatment analysis for change from baseline in WASO (min) to Month 3 (Daridorexant 25 mg vs placebo).p-value: <0.000195% CI: [-17.494, -6.23]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in WASO (min) to Month 3 (Daridorexant 50 mg vs placebo).p-value: <0.000195% CI: [-23.945, -12.661]Mixed Models Analysis
Secondary
Change From Baseline to Month 1 in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score
The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.
Time frame: From baseline to Month 1 (i.e. for up to 1 month)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 1 in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score | -2.77 Scores on a scale |
| Daridorexant 50 mg | Change From Baseline to Month 1 in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score | -3.77 Scores on a scale |
| Placebo | Change From Baseline to Month 1 in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score | -2.02 Scores on a scale |
Comparison: Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 1 (Daridorexant 25 mg vs placebo).p-value: =0.054795% CI: [-1.515, 0.015]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 1 (Daridorexant 50 mg vs placebo).p-value: <0.0000195% CI: [-2.508, -0.983]Mixed Models Analysis
Secondary
Change From Baseline to Month 1 in the Subjective Total Sleep Time (sTST)
Subjective Total Sleep Time is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time.
Time frame: From baseline to Month 1 (i.e. for up to 1 month)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 1 in the Subjective Total Sleep Time (sTST) | 34.18 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 1 in the Subjective Total Sleep Time (sTST) | 43.62 minutes |
| Placebo | Change From Baseline to Month 1 in the Subjective Total Sleep Time (sTST) | 21.56 minutes |
Comparison: Between-treatment analysis for change from baseline in sTST (min) to Month 1 (Daridorexant 25 mg vs placebo).p-value: =0.001395% CI: [4.953, 20.288]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in sTST (min) to Month 1 (Daridorexant 25 mg vs placebo).p-value: <0.000195% CI: [14.405, 29.708]Mixed Models Analysis
Secondary
Change From Baseline to Month 3 in IDSIQ Sleepiness Domain Score
The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.
Time frame: From baseline to Month 3 (i.e. for up to 3 months)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 3 in IDSIQ Sleepiness Domain Score | -4.78 Scores on a scale |
| Daridorexant 50 mg | Change From Baseline to Month 3 in IDSIQ Sleepiness Domain Score | -5.70 Scores on a scale |
| Placebo | Change From Baseline to Month 3 in IDSIQ Sleepiness Domain Score | -3.79 Scores on a scale |
Comparison: Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 3 (Daridorexant 25 mg vs placebo).p-value: 0.053495% CI: [-1.99, 0.014]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 3 (Daridorexant 50 mg vs placebo).p-value: =0.000295% CI: [-2.905, -0.905]Mixed Models Analysis
Secondary
Change From Baseline to Month 3 in the Subjective Total Sleep Time (sTST)
Subjective Total Sleep Time is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time.
Time frame: From baseline to Month 3 (i.e. for up to 3 months)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 3 in the Subjective Total Sleep Time (sTST) | 47.83 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 3 in the Subjective Total Sleep Time (sTST) | 57.67 minutes |
| Placebo | Change From Baseline to Month 3 in the Subjective Total Sleep Time (sTST) | 37.90 minutes |
Comparison: Between-treatment analysis for change from baseline in sTST (min) to Month 3 (Daridorexant 25 mg vs placebo).p-value: =0.033495% CI: [0.782, 19.082]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in sTST (min) to Month 3 (Daridorexant 50 mg vs placebo).p-value: <0.0000195% CI: [10.623, 28.918]Mixed Models Analysis
Post Hoc
Change From Baseline to Month 1 in Log-transformed LPS (LSGM Ratio to Baseline)
Post-hoc analyses were performed using log-transformed LPS data, as the LPS values at baseline more closely resembled a log-normal distribution (skewed to the right) than a normal distribution.
Time frame: From baseline to Month 1 (i.e. for up to 1 month)
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 1 in Log-transformed LPS (LSGM Ratio to Baseline) | 0.49 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 1 in Log-transformed LPS (LSGM Ratio to Baseline) | 0.45 minutes |
| Placebo | Change From Baseline to Month 1 in Log-transformed LPS (LSGM Ratio to Baseline) | 0.62 minutes |
Comparison: Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 1 (Daridorexant 25 mg vs placebo).p-value: 0.000395% CI: [0.7, 0.9]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 1 (Daridorexant 50 mg vs placebo).p-value: <0.000195% CI: [0.65, 0.82]Mixed Models Analysis
Post Hoc
Change From Baseline to Month 3 in Log-transformed LPS (LSGM Ratio to Baseline)
Post-hoc analyses were performed using log-transformed LPS data, as the LPS values at baseline more closely resembled a log-normal distribution (skewed to the right) than a normal distribution.
Time frame: From baseline to Month 3 (i.e. for up to 3 month)
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Daridorexant 25 mg | Change From Baseline to Month 3 in Log-transformed LPS (LSGM Ratio to Baseline) | 0.43 minutes |
| Daridorexant 50 mg | Change From Baseline to Month 3 in Log-transformed LPS (LSGM Ratio to Baseline) | 0.41 minutes |
| Placebo | Change From Baseline to Month 3 in Log-transformed LPS (LSGM Ratio to Baseline) | 0.56 minutes |
Comparison: Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 3 (Daridorexant 25 mg vs placebo).p-value: 0.000295% CI: [0.68, 0.89]Mixed Models Analysis
Comparison: Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 3 (Daridorexant 50 mg vs placebo).p-value: <0.000195% CI: [0.64, 0.83]Mixed Models Analysis